Physicochemical properties, cytotoxic activity and topoisomerase ii inhibition of 2,3-diaza-anthracenediones

Isabella, P De; Palumbo, Manlio; Sissi, Claudia; Carenini, Nives; Capranico, Giovanni; Menta, Ernesto; Oliva, Ambrogio; Spinelli, Silvano; Krapcho, A. Paul; Giuliani, F; Zunino, Franco

doi:10.1016/s0006-2952(96)00646-6

Cited by 25 publications

(20 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this case, it is safe to conclude that the C 3 N bioisosteric substitution at the central ring was primarily responsible for the reduced cleavage activity. In agreement with this result, a double C 3 N bioisosteric substitution in anthracenediones (including mitoxantrone) has been shown to abolish topoisomerase poisoning activity (29).…”

Section: Discussionsupporting

confidence: 53%

Mapping Drug Interactions at the Covalent Topoisomerase II-DNA Complex by Bisantrene/Amsacrine Congeners

Capranico

Guano

Moro³

et al. 1998

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

To identify structural determinants for the sequencespecific recognition of covalent topoisomerase II-DNA complexes by anti-cancer drugs, we investigated a number of bisantrene congeners, including a 10-azabioisoster, bearing one or two 4,5-dihydro-1H-imidazol-2-yl hydrazone side chains at positions 1, 4, or 9 of the anthracene ring system. The studied bisantrene/amsacrine (m-AMSA) hybrid and bisantrene isomers were able to poison DNA topoisomerase II with an intermediate activity between those of bisantrene and m-AMSA. Moving the side chain from the central to a lateral ring (from C-9 to C-1/C-4) only slightly modified the drug DNA affinity, whereas it dramatically affected local base preferences of poison-stimulated DNA cleavage. In contrast, switching the planar aromatic systems of bisantrene and m-AMSA did not substantially alter the sequence specificity of drug action. A computer-assisted steric and electrostatic alignment analysis of the test compounds was in agreement with the experimental data, since a common pharmacophore was shared by bisantrene, m-AMSA, and 9-substituted analogs, whereas the 1-substituted isomer showed a radically changed pharmacophoric structure. Thus, the relative space occupancy and electron distribution of putative DNA binding (aromatic rings) and enzyme binding (side chains) moieties are fundamental in directing the specific action of topoisomerase II poisons and in determining the poison pharmacophore.The elucidation of structural determinants of the sequencespecific recognition of DNA by small molecules is fundamental for a rational design of gene-specific DNA binders that are effective in the therapy of human diseases. Several DNA-interactive compounds are known that may bind to the double helix in a site-selective manner; however, the degree and mechanisms of the specificity are very different among them (1-4). A wide variety of antitumor drugs, with and without the ability to bind to naked DNA, have been shown to poison DNA topoisomerases with a high sequence selectivity (2, 5-7). DNA topoisomerases are ubiquitous enzymes deputed to resolve topological problems that arise during various nuclear processes including transcription, recombination, and chromosome partitioning at cell division (8 -10). Type II enzymes make transient double-stranded breaks into one segment of DNA and pass an intact duplex through the broken DNA, before resealing the break (2, 8 -10). Anticancer agents able to poison the mammalian enzymes stabilize a key intermediate of the catalytic reaction wherein DNA strands are broken and covalently linked to the protein. Thus, the poisoning action results in increased DNA cleavage levels in living cells that eventually trigger a cell death process.Classical topoisomerase poisons stimulate DNA cleavage in a sequence-selective manner, yielding drug-specific cleavage intensity patterns in agarose as well as sequencing gels (2,5,6,11,12). Each pattern reflects the recognition of specific features of the enzyme-DNA covalent complex that are likely dictated by the n...

show abstract

Section: Discussionsupporting

confidence: 53%

Mapping Drug Interactions at the Covalent Topoisomerase II-DNA Complex by Bisantrene/Amsacrine Congeners

Capranico

Guano

Moro³

et al. 1998

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…9,10 However, it has also been proposed that anthracenedione drugs containing side chain amine groups can induce apoptosis in cancer cells through formation of a covalent adduct with the N-2 amino group of a guanine residue at CpG sites after activation by formaldehyde. [14][15][16] The results of this study confirm that daunorubicin, mitoxantrone and pixantrone can form covalent adducts with duplex DNA.…”

Section: Discussionmentioning

confidence: 99%

Reversible and formaldehyde-mediated covalent binding of a bis-amino mitoxantrone analogue to DNA

et al. 2016

View full text Add to dashboard Cite

Collins, J. (2016). Reversible and formaldehyde-mediated covalent binding of a bis-amino mitoxantrone analogue to DNA. Organic and Biomolecular Chemistry, 14 (20), 4728-4738. Reversible and formaldehyde-mediated covalent binding of a bis-amino mitoxantrone analogue to DNA AbstractThe ability of a bis-amino mitoxantrone anticancer drug (named WEHI-150) to form covalent adducts with DNA, after activation by formaldehyde, has been studied by electrospray ionisation mass spectrometry and HPLC. Mass spectrometry results showed that WEHI-150 could form covalent adducts with d(ACGCGCGT)2 that contained one, two or three covalent links to the octanucleotide, whereas the control drugs (daunorubicin and the anthracenediones mitoxantrone and pixantrone) only formed adducts with one covalent link to the octanucleotide. HPLC was used to examine the extent of covalent bond formation of WEHI-150 with d(CGCGCG)2 and d(CG5MeCGCG)2. Incubation of WEHI-150 with d(CG5MeCGCG)2 in the presence of formaldehyde resulted in the formation of significantly greater amounts of covalent adducts than was observed with d(CGCGCG)2. In order to understand the observed increase of covalent adducts with d(CG5MeCGCG)2, an NMR study of the reversible interaction of WEHI-150 at both CpG and 5MeCpG sites was undertaken. Intermolecular NOEs were observed in the NOESY spectra of d(ACGGCCGT)2 with added WEHI-150 that indicated that the drug selectively intercalated at the CpG sites and from the major groove. In particular, NOEs were observed from the WEHI-150 H2,3 protons to the H1′ protons of G3 and G7 and from the H6,7 protons to the H5 protons of C2 and C6. By contrast, intermolecular NOEs were observed between the WEHI-150 H2,3 protons to the H2′′ proton of the 5MeC3 in d(CG5MeCGCG)2, and between the drug aliphatic protons and the H1′ proton of G4. This demonstrated that WEHI-150 preferentially intercalates at 5MeCpG sites, compared to CpG sequences, and predominantly via the minor groove at the 5MeCpG site. The results of this study demonstrate that WEHI-150 is likely to form interstrand DNA cross-links, upon activation by formaldehyde, and consequently exhibit greater cytotoxicity than other current anthracenedione drugs. Disciplines Medicine and Health Sciences | Social and Behavioral Sciences Publication DetailsKonda, S., Kelso, C., Pumuye, P. P., Medan, J., Sleebs, B. E., Cutts, S. M., Phillips, D. R. & Collins, J. (2016

show abstract

“…Mitoxantrone is useful for chemotherapy because it inhibits both DNA replication and DNA-dependent RNA synthesis by intercalating into DNA and causing crosslinking and strand breaks. 41,42) It also inhibits topoisomerase II and consequently interferes with DNA repair. [42][43][44] Previous SAR studies have indicated the crucial role of diaminoalkyl group in side chains of anthraquinones for their cytotoxic activities, 44,45) but the importance of this diaminoalkyl group for any of the proposed mechanisms of action is still not clear.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Human Telomerase Inhibition of a Series of Regioisomeric Disubstituted Amidoanthraquinones

Huang

Chen

Huang

et al. 2007

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

Most human somatic cells divide 50-60 times before senescence occurs. These cells invariably enter a state of irreversibly arrested growth. This process, termed replicative senescence, is thought to be a tumor-suppressive mechanism and an underlying cause of aging.1) The molecular mechanism underlying cellular senescence has been characterized. It is well accepted that telomeres play a major role in the process. Telomeres are the physical ends of linear eukaryotic chromosomes. They consist of hundreds to thousands of tandem repeats of the sequence TTAGGG, that are essential for stabilizing chromosomes.2) Because conventional DNA polymerase cannot replicate the very end of chromosomes, telomere length is shortened upon each DNA replication. Telomerase is the enzyme activity that elongates short telomeres. Because telomerase activity is low or not detectable in most normal human somatic cells, telomeric DNA is progressively shortened with each cell division. The shortened telomeres then signal cells to enter senescence through a DNA damage signaling pathway. Telomere length is considered as a biological clock that is capable of determining the proliferative capacity of most human somatic cells. 3,4)While telomerase is not detected or is low in most of the normal human cells, it is detected in ca. 85-90% of the immortalized or tumor cells. In humans, telomerase activity is tightly regulated by expression of the human telomerase reverse transcriptase (hTERT) gene, which appears to be the key regulator for telomerase activity. Inhibition or activation of the hTERT expression could profoundly affect the proliferative capacity of normal cells and cancers.5-7) Because telomerase is required for the sustained proliferation of most immortal cells, including cancer cells, it has become the focus of much attention as a novel and potentially highlyspecific target for the development of new anticancer chemotherapeutics. In this respect, antisense oligonucleotides or small molecular inhibitors have been identified as inhibitors to telomerase. 8) Several of them effectively inhibit telomerase in vitro and limit the proliferation of cancer cells in vivo.9) However, because a lag period is required for telomeres to be shortened to critical short length, the clinical applicability of telomerase inhibitor was questioned. For example, it takes ca. 20 additional cell divisions for telomeres of HeLa cells to be shortened to critical length.8) It is not realistic for telomerase inhibitor to be used in treating cancers. Thus, it was proposed that telomerase inhibitors should work with other chemotherapeutic agents for treating cancers.10)The use of cytotoxic agents to kill cancer cells and telomerase inhibitor to limit the proliferative potential of residual cancer cells should be a better approach in cancer chemotherapy. Interestingly, guanine-quadruplex (G-quadruplex) stabilizers such as 2,6-pyridine-dicarboxamide derivatives and 3,6,9-trisubstituted acridine compounds caused accelerated senescence in cancer cells. Molecules able to s...

show abstract

Physicochemical properties, cytotoxic activity and topoisomerase ii inhibition of 2,3-diaza-anthracenediones

Cited by 25 publications

References 23 publications

Mapping Drug Interactions at the Covalent Topoisomerase II-DNA Complex by Bisantrene/Amsacrine Congeners

Mapping Drug Interactions at the Covalent Topoisomerase II-DNA Complex by Bisantrene/Amsacrine Congeners

Reversible and formaldehyde-mediated covalent binding of a bis-amino mitoxantrone analogue to DNA

Synthesis and Human Telomerase Inhibition of a Series of Regioisomeric Disubstituted Amidoanthraquinones

Contact Info

Product

Resources

About